The Clinical Psychopharmacology Section conducts preclinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK and NIMH, is the synthesis and evaluation of potential treatment medications for cocaine addiction. The strong association of high risk behaviors related to the spread of HIV with cocaine addiction makes the effort to develop cocaine treatment medications highly related to the fight against AIDS. In this fiscal year we continued the effort to develop analogs of GBR12909 as putative cocaine antagonists or cocaine substitution-type medications. Studies in Rhesus monkeys reported last year showed that daily administration of GBR12909 suppresses cocaine self-administration without the development of tolerance. Other studies showed unique effects of GBR12909 in an animal model of sensitization. In this fiscal year we developed a long-acting decanoate analog of GBR12909. A single administration of this agent to monkeys reduced cocaine self- administration for almost four weeks. Other efforts identified the clinically available medications,phentermine and fenfluramine, as potential treatment agents for cocaine addiction. In collaboration with Dr. Mash and others, our lab helped characterize the neurochemical and neuroendocrine effects of the potential treatment agent, ibogaine. Other studies identified a novel cocaine binding site in human brain. Clinical and laboratory experiments demonstrated robust changes in the serotonergic systems during cocaine withdrawal. These results support the hypothesis that cocaine withdrawal is associated with a dual deficit of dopamine and serotonin and provide a strong rationale for the treatment of cocaine addiction with medications which release both dopamine(phentermine) and serotonin (fenfluramine).